The RFA solicits applications to identify all of the sequence-based functional elements in the Caenorhabditis elegans and/or Drosophila melanogaster genomes.

$16.5 million dollars in FY 2007 funds have been committed to fund this RFA.

Between 6 and 12 awards will be made.

This RFA will use the NIH U01 Research Project Cooperative Agreement award mechanism.

Eligible organizations include for-profit and non-profit organizations, public and private institutions, units of state and local governments, eligible federal agencies, and foreign and domestic institutions.

Eligible principal investigators include any individual with the skills, knowledge, and resources necessary to carry out the proposed research.

Applicants may submit more than one application, provided they are scientifically distinct.

The purpose of this RFA is to solicit applications for a set of research projects that will constitute a Research Consortium that will conduct experiments to identify all of the sequence-based functional elements in the Caenorhabditis elegans and/or Drosophila melanogaster genomes. Both computational and experimental approaches will be critical components of these efforts. The Research Consortium will be separate from, but affiliated with, the existing ENCODE (Encyclopedia of DNA Elements) Consortium that is directed toward the human genome and is currently in a pilot phase focused on locating all of the sequence-based functional elements in a selected 1% of that genome. This RFA is being issued in conjunction with a second RFA-HG-06-007, “A Data Coordination Center for the modENCODE Project”, which will support the database needs of this project.

With the availability of a complete, high quality genomic sequence of an organism, one of the next major challenges for genome biology is to generate a comprehensive catalog of all of the sequence-based functional elements encoded in that DNA. Toward this end, in 2003, the NHGRI launched the Encyclopedia of DNA Elements (ENCODE) Project (http://www.genome.gov/ENCODE), the long-term goal of which is to identify all of the sequence-based functional elements in the human genome. This project began with a pilot phase in which a defined 1% (30 Mb) of the human genome sequence is being analyzed. The ENCODE Project also included a technology development effort, with the purpose of expanding the repertoire of high-throughput methods available for the identification of sequence-based functional elements. While significant knowledge will be developed by the ENCODE pilot project, studying the human genome imposes some serious limitations. One is the difficulty of validating the biological relevance of the elements discovered, as many of the necessary experiments cannot be done with humans. Also, because the ENCODE pilot addresses only 1% of the human genome, it is also limited in its ability to test the efficacy of technologies that can only be applied on a genome-wide basis.

These limitations would not pertain to an effort to identify all of the sequence-based functional elements in the genome of certain model organisms, specifically those with a genome that is small enough to allow most current technologies to be applied and which can be used in experimental studies. At present, there are some modestly sized research projects that are focused on identifying functional elements in the genomes of a few of the best-studied non-vertebrate model organisms. For example, an effort is underway to identify and clone representative full-length cDNAs for every gene in D. melanogaster, and genomes of related Drosophila species are being sequenced to identify sequence elements conserved during evolution. While such efforts are proceeding rapidly, NHGRI has concluded that there would be significant benefit to a coordinated effort that encourages multiple groups to work together to address the entire genome of an important model organism. Having such a comprehensive data set on the functional elements in a well-studied model organism would help provide important insights into the biology of the organism under study as well as other organisms, including the human. It would also stimulate new and more effective methods for storing, displaying and analyzing genome-wide data.

With the issuance of this RFA, NHGRI announces its intention to initiate a model organism ENCODE Project (modENCODE) to find all of the functional sequence-based elements in the entire genome of either or both of the very widely used multicellular model organisms with finished genome sequences, Caenorhabditis elegans and Drosophila melanogaster. Because of the nature of these two organisms as laboratory systems, the scope of modENCODE will be somewhat broader than that of the ENCODE. modENCODE will address the entire genome of the target organism(s). It will also make use of the experimental opportunities offered by the model system(s) not only to allow discovery, but also to promote further understanding of functional elements in ways that would not be possible with the human or even other mammalian systems. Applicants may propose to work on either or both organisms. Based in large measure on the efforts proposed and on the determination of the scientific quality by peer review of the proposals, NHGRI will decide whether the modENCODE Project will include one or both organisms. In making this decision, NHGRI will also consider: 1) the possibility that an effort including both organisms could achieve synergies that would not be obtained if only one were pursued, 2) the potential lost opportunities in choosing one organism and not both, and 3) whether the available funds will be sufficient to do a credible job on analyzing both organisms or whether the biomedical research enterprise would be best served by a more detailed analysis of one of them.

This RFA solicits applications that will coordinate and augment ongoing research efforts to identify all of the functional elements in the genome(s) of C. elegans and/or D. melanogaster and support the biological validation of these elements.

The sequence-based functional elements that will be targeted include, but are not limited to:

Transcribed sequences, including both protein coding and non-protein coding sequences. A description of gene structure with transcription start sites and polyadenylation sites, along with all biologically relevant alternative transcripts, is an example.

DNA sequence features that affect/control chromosome biology. Examples include origins of replication and hot spots for recombination.

Epigenetic marks, such as DNA methylation and chromatin modifications.

Sequence variations that have a functional consequence and are associated with a functional element; modENCODE will not support polymorphism detection alone.

Sequencing the genomes of related species or strains of C. elegans and D. melanogaster is outside the scope of this RFA. For more information about how NHGRI supports the genomic sequencing of other organisms, see http://www.genome.gov/10002189.

Applicants will be expected to propose experiments that apply high-throughput methods to comprehensively, accurately and efficiently identify the entire set of one or more types of functional elements contained within the model organism genome. The proposal should document the applicant’s 1) expertise in working with the proposed model organism, 2) experience with the technology being proposed 3) bioinformatics expertise and the bioinformatics infrastructure needed to support the project and 4) experience with large-scale data production. Applicants are also encouraged to include efforts to improve the performance of the method(s) or technology(ies) being applied during the course of the research project in order to, for example, reduce cost or increase quality or throughput. The formation of collaborations to bring together all of the necessary expertise to carry out a comprehensive analysis of the genomic complement of one or more functional elements is acceptable.

Through the modENCODE Project, NHGRI intends to support the generation of a comprehensive catalog of sequence-based functional elements in either or both the C. elegans and D. melanogaster genomes using high-throughput methods that measure biochemical events. Since this catalog of functional elements will subsequently serve as a reference data set that will be used in a wide range of studies, the quality, comprehensiveness, and biological relevance of the modENCODE data will be critical to the success of the project.

Quality. The authenticity of the biochemical events detected by the primary experimental approach must be confirmed using a one or more, preferably completely independent, validation methods. To the extent they are available, the validation methods employed should also be cost-effective, efficient and high throughput. Even if such methods are available, validation will add significant time and cost to the project. To control such costs, it will be sufficient for the applicant to propose validating only that fraction of identified elements that is needed to provide a 95% confidence level that the detected biochemical events occur in vivo. If the applicant believes that the 95% confidence level is inappropriate, s/he should propose and justify a different level of confidence.

Comprehensiveness. In addition to being comprised of very high quality data, the catalog generated by modENCODE must be as comprehensive as possible. Thus, the applicant should address the ability of the proposed approach(es) to identify a significant fraction of the instances of the functional element under investigation in the genome of study. NHGRI recognizes that this is potentially difficult, as the actual number of such elements in a genome is generally not known, and there is no “gold standard” for comparison of data across the entire genome. However, the applicant should attempt to provide a reasonable estimate of the sensitivity of the proposed approach(es) and discuss the basis for the estimate. This may involve identification of the functional elements using an independent method for comparison and/or information from the literature.

Biological relevance. Once a catalog of biochemically validated elements is created, it will be necessary to demonstrate the biological relevance of the elements within the collection, i.e., to show that the sequences identified as being members of a particular functional class actually do have the inferred function. Thus, the applicant must describe in detail how the biological authenticity of the identified elements will be validated. As above, these studies of biological relevance should be limited to that fraction of elements needed to confirm the functional role of the class of elements. While this aspect of the program is intended to extend the scope of this project beyond that of ENCODE by including analysis of the function of detected elements as a class, it is not intended to support a detailed determination of the biological function of individual elements. NHGRI recognizes that, eventually, the research community will want to know the precise biological role that each of the individual elements plays in the biology of the organism, but that the studies that will be necessary to uncover these roles may best be done in individual laboratories rather than by a large-scale effort. Furthermore, such studies will require a significant investment that is beyond what is currently available for the modENCODE initiative; therefore, they are considered outside of the scope of this RFA. Instead, what the modENCODE initiative will require is a statistically valid demonstration that the majority of the members of the type of element being determined do have the function attributed to that type.

The applicant should present a discussion of the functional element(s) to be identified and a detailed experimental plan that will serve to find all of the instances of the element(s) in the genome. The experimental plan should address, but not be limited to, the following:

the specific assay(s) to be used, including the strengths and limitations;

a description of quantitative data standards for each technology proposed;

preliminary data demonstrating the efficiency of each technology proposed, as well as its specificity (defined here as the false positive rate) and sensitivity (defined here as the false negative rate), focusing on how the proposed approach will maximize the discovery of authentic elements in the genome while minimizing the contamination of the data set with non-functional sequences; a definition of the quantitative data standards that were used to arrive at the sensitivity and specificity should be included;

a plan for scaling up to the level of effort required to analyze the entire genome while maintaining quality and consistency of data, including a discussion of anticipated economies of scale and comprehensiveness;

detailed plans for biochemical validation and determination of biological relevance;

a detailed analysis of the total costs needed to carry out the proposed experiments; and

approach(es) to the collection and processing of data from the experiments.

Discovery methods and validation methods that take advantage of existing resources and biological knowledge (e.g., data in databases and the literature) are strongly encouraged. However, NHGRI recognizes that it may be necessary to generate a new set of reagents or physical resources, such as specific clone libraries or transgenic animals, to carry out the proposed analyses. Generation of such resources should be proposed only to the extent that they are needed to identify or validate the target functional elements. The creation of a set of physical resources for the primary purpose of generating a community resource independent of discovery or validation studies will not be supported. For example, a proposal to generate a collection of gene knockouts for all genes in the C. elegans genome would not be responsive to this RFA, but generation of a sufficient number of knockouts to validate the biological authenticity of a set of identified microRNA-encoding sequences would be considered to be responsive. Since the validation experiments should not address the entire genome, the generation of reagents or resources needed for validation studies should be limited to the extent necessary to conduct them, unless it can be demonstrated that it would be significantly more efficient, in terms of unit costs, to generate a complete set of reagents than to generate a subset.

In practice, achieving a ‘complete’ catalog of functional elements is likely not to be feasible. In most cases, a subset of each class of functional element will express that function (and be detectable) in one or a restricted set of tissues or in a developmentally–specific manner or in response to specific environmental challenges, and it will not be practical to study every tissue, developmental stage or environmental condition. The applicant should propose a set of experimental conditions (e.g., cell lines, embryos of specific developmental stages, specific tissues, pools of embryos or tissues, or whole animals) that will maximize the discovery of functional elements to the point of diminishing returns, i.e., at which the cost/benefit ratio is no longer favorable. Once awards are made, the modENCODE Consortium will agree on a set of experimental conditions for the project and the generation and/or use of common reagents, as needed.

The modENCODE Project will function as a Research Consortium. The Consortium will be open to all academic, government and private sector scientists willing to participate in an open process to facilitate the comprehensive annotation of these model organism genomes. It is expected that groups with funding from other sources will be able to participate in the modENCODE Project and, therefore, funding through this initiative is not a prerequisite for participation in this Consortium. Awardees funded through the concurrent RFA, HG-06-007, “A Data Coordination Center for the modENCODE Project,” which will support the database needs of modENCODE, will also participate in the Research Consortium.

This funding opportunity will use the NIH U01 Research Project Cooperative Agreement award mechanism. In the cooperative agreement mechanisms, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing their components of the modENCODE Project, with NIH staff being substantially involved as a partner with the Principal Investigators, as described under the Section VI. 2. Administrative Requirements, Cooperative Agreement Terms and Conditions of Award". This RFA is a one-time solicitation. At the current time, NHGRI anticipates that this will be a three-year project unless circumstances warrant a continuation of this effort.

2. Funds Available

The NHGRI intends to commit approximately $16.5 million dollars in FY 2007 to fund 6 to 12 new grants in response to this RFA. An applicant may request a project period of up to 3 years. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size of each award will also vary. It is expected that the size of the awards will range from approximately $250,000 to $2 million direct costs per year; however, these are estimates and not budgetary limits. Although the financial plans of NHGRI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. The earliest anticipated award date is March 1, 2007.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

For-profit organizations

Non-profit organizations

Public or private institutions, such as universities, colleges, hospitals, and laboratories

Units of State government

Units of local government

Eligible agencies of the Federal government

Foreign Institutions

Domestic Institutions

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs.

2. Cost Sharing or Matching

No cost sharing or matching is required for applications submitted in response to this RFA.

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

Foreign Organizations

Several special provisions apply to applications submitted by foreign organizations:

Charge back of customs and import fees is not allowed.

Format: every effort should be made to comply with the format specifications, which are based upon a standard US paper size of 8.5" x 11."

Prospective applicants are asked to submit a letter of intent that includes the following information:

Descriptive title of proposed research

Name, address, and telephone number of the Principal Investigator

Names and Institutions of other key personnel

Participating institutions

Number and title of this funding opportunity

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed at the beginning of this document.

Applications must be prepared using the research grant applications found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, andthreesigned photocopies in one package to:

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the NHGRI.Incomplete and non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight (8) weeks.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

Pre-Award Costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm.

6. Other Submission Requirements Not Applicable

Plan for Sharing Research Data

The NHGRI is committed to the principle of rapid data release to the scientific community. This principle was initially implemented during the Human Genome Project and has been recognized as leading to one of the most effective ways of promoting the use of the genome sequence data to advance scientific knowledge. At a meeting in Ft. Lauderdale, FL that was co-sponsored by the Wellcome Trust and NHGRI in January 2003, the concept of rapid data release by genomic sequence data producers was reaffirmed, and the attendees strongly recommended applying the practice to other types of data produced by “community resource projects”. The attendees recognized, however, that different issues, particularly with respect to data validation, would be involved in the development of appropriate release practices for different types of data. Since they also recognized that sustaining the practice of rapid, prepublication data release by community resources requires that the interests of all involved - including the data producers, data users, and funding agencies - be addressed, they emphasized the need to develop a tripartite system of responsibility. The meeting report from the Ft. Lauderdale meeting can be found on the Wellcome Trust website at: http://www.wellcome.ac.uk/doc_wtd003208.html.

The NHGRI has identified the modENCODE Project as a community resource project. As such, the modENCODE Project aims to function openly by making all data available to the scientific community in a timely manner prior to publication. It is expected that the modENCODE Consortium will establish a common data release policy and that all participants will agree to abide by that policy. The human ENCODE Consortium established a data release policy that the NHGRI deems would be appropriate for the modENCODE Project as well (see http://www.genome.gov/12513440). The applicant should provide specific plans for data release in the application.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

As the modENCODE Project is a community resource project, NHGRI expects that not only data, but also resources generated during the course of the program should be made rapidly available to the research community and that sharing plans should follow the same principles and spirit as the rapid data release policy. The applicant should provide specific plans for resource sharing and distribution in the application.

Section V. Application Review Information

1. Criteria

The following will be considered in making funding decisions:

Scientific merit of the proposed project as determined by peer review

Availability of funds

Relevance of program priorities

Synergy with other funded projects

2. Review and Selection Process

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NHGRI in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score.

Receive a written critique.

Receive a second level of review by the National Advisory Council for Human Genome Research

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts, methods or technologies that drive this field?Does the application address the goals and objectives outlined in the RFA?

Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Does the applicant intend to study the entire genome of the proposed model organism? Are the plans for achieving comprehensiveness and plans for validation reasonable?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?Does the project develop new methods or technologies to reduce costs or increase quality or throughput?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)? Do the investigators have the necessary expertise in working with the model organism(s), implementing the proposed high-throughput technology, and providing the necessary bioinformatics support? Do the investigators have experience with large-scale data generation?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?Is the bioinformatics infrastructure sufficient to accomplish the goals of the project?

2.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy.

The NHGRI has identified the modENCODE Project is a community resource project (see Section IV.6). As such, the modENCODE Project aims to function openly by making all data available to the scientific community in a timely manner prior to publication. It is expected that the modENCODE Consortium will establish a common data release policy and that all participants will agree to abide by that policy. The human ENCODE Consortium established a data release policy that the NHGRI deems would be appropriate for the modENCODE Project as well (see http://www.genome.gov/12513440). The applicant should provide specific plans for data release in the application and indicate his/her willingness to abide by the data release policy that will eventually be adopted by the modENCODE Consortium.

Program staff will be responsible for the administrative review of the plan for sharing data. The adequacy of the data sharing plan will be considered by program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data sharing plan with the awardee before recommending funding of an application. The final negotiated version of the data sharing plan will become a condition of the award of the cooperative agreement. The effectiveness of the data sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the resource sharing plan with the awardee before recommending funding of an application. The final negotiated version of the resource sharing plan will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

3. Anticipated Announcement and Award DatesNot Applicable

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the Principle Investigator will be able to access his or her Summary Statement (written critique) via the eRA Commons.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm).

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 12 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

There will be terms and conditions on the awards pertaining to data policy and resources release policy (where applicable) that have agreed upon by the applicant and the program staff.

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

The following terms and conditions will be incorporated into the award statement of each cooperative agreement awarded under RFA HG-06-006 and will be provided to the Principal Investigator and the appropriate institutional officials at the time of award. The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instruments used for this program will be the NIH U01 Research Project Cooperative Agreement award mechanism.The cooperative agreement is an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and programmatic involvement with the awardee is anticipated during the performance of the activity. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility reside with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

2.A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator will have the primary responsibility for defining the details for the project within the guidelines of RFA HG-06-006 and for performing the scientific activities. The P.I. will agree to accept close coordination, cooperation and participation of NIH staff in those aspects of scientific and technical management of the project as described under "NIH Responsibilities".

Analyze the entire genome of the model organism and not just a portion of the genome; OR, lead a research group composed of several individuals with a shared experimental approach with each individual examining a part of the genome, provided that the group as a whole will gather data on the entire genome and that the P.I. will take responsibility for ensuring this.

Share results according to the data sharing policy developed for and by this project.

Participate in group activities, including attending periodic workshops to discuss the project's progress and coordinating the publication of research results.

Fully disclose all algorithms, software source code and experimental methods to the other members of the consortium for purposes of scientific evaluation.

Not disclose confidential information obtained from other members of the consortium.

Adhere to NHGRI policies regarding intellectual property and other policies that might be established during the course of this activity.

Submit periodic progress reports in a standard format, as agreed upon by the modENCODE Coordinating Committee (mECC) and Scientific Advisory Panel.

Accept and implement the common guidelines and procedures approved by the mECC, Scientific Advisory Panel and NHGRI.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

2.A.2. NIH Responsibilities

The NIH Project Scientist is a scientist of the NHGRI extramural staff who will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination. However, the role of NIH staff will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus of the mECC and that NIH staff will be given the opportunity to offer input to this process. One NHGRI Project Scientist will participate as a member of the mECC and will have one vote. The Project Scientist will have the following substantial involvement:

Participate with the other mECC members in the group process of setting research priorities, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted. The Project Scientist will assist and facilitate the group process and not direct it.

Serve as a liaison, helping to coordinate activities among and for the awardees, including acting as a liaison to the NHGRI, and as an information resource about extramural genome research activities. The Project Scientist will also coordinate the efforts of the modENCODE Consortium with groups participating in the ENCODE Consortium.

Attend all mECC meetings as a voting member and assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action. The Project Scientist must be informed of all major interactions of members of the mECC. The NIH Project Scientist will be responsible for scheduling the time and preparing concise minutes or summaries of the mECC meetings, which will be delivered to members of the group within 30 days after each meeting.

Report periodically on the progress of the modENCODE Project to the Director, NHGRI and to the National Advisory Council for Human Genome Research.

Provide relevant expertise and overall knowledge of NIH-sponsored research to facilitate the selection of scientists not affiliated with the awardee institutions to serve on the Scientific Advisory Panel.

Serve as a liaison between the mECC and the Scientific Advisory Panel, attending Scientific Advisory Panel meetings in a non-voting liaison member role.

Serve on subcommittees of the mECC and the Scientific Advisory Panel, as appropriate.

Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action.

Provide advice in the management and technical performance of the investigation.

Assist in promoting the availability of the modENCODE data and related resources developed in the course of this project to the scientific community at large.

Participate in data analyses, interpretations, and, where warranted, co-authorship of the publication of results of studies conducted through the modENCODE Research Consortium.

Additionally, an NHGRI program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the NoA. The NHGRI program director may also serve as the NHGRI Project Scientist.

2.A.3. Collaborative Responsibilities

The mECC will serve as the main governing board of the modENCODE Research Consortium established under this RFA. The mECC will be responsible for coordinating the activities being conducted by the modENCODE Research Consortium. The Coordinating Committee membership will include one NIH Project Scientist and the P.I. from each awarded cooperative agreement. The awardee funded through the concurrent RFA, HG-06-007, “A Data Coordination Center for the modENCODE Project” which will support the database needs of this project, will also participate in the Research Consortium and be a member of the mECC. The mECC may add additional members. Other government staff may attend the mECC meetings, if their expertise is required for specific discussions. It is anticipated that additional coordination mechanisms will be set up with other U.S. and international groups that may join the modENCODE effort.

To address particular issues, the mECC may establish working groups as needed, which will include representatives from the Research Consortium and the NHGRI and possibly other experts. Such groups might include ones to: 1) develop a list of common reagents needed for the modENCODE Project; 2) address data management issues; 3) analyze modENCODE data; 4) develop quality standards and methods to assess data quality; and 5) handle communication issues and develop principles for reporting findings.

A Scientific Advisory Panel (SAP) will be established by the NHGRI to evaluate the progress of the modENCODE Research Consortium. The SAP will provide recommendations to the Director, NHGRI and the National Advisory Council for Human Genome Research about the progress and scientific direction of all components of the modENCODE program. The SAP will be composed of six to eight senior scientists with relevant expertise, although the membership may be enlarged permanently or on an ad hoc basis as needed.

The SAP will meet at least twice a year; some meetings may be conducted by telephone conference. At least once a year, there will be a joint meeting with the mECC to allow the members of the both the SAP and the mECC to interact directly with each other. Twice a year the SAP will make recommendations regarding progress of the modENCODE Research Consortium and present advice to the Director of NHGRI and the National Advisory Council for Human Genome Research about changes, if any, which may be necessary in the modENCODE program.

2.A.4. Arbitration Process

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be convened: a designee of the Coordinating Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit electronically quarterly reports that describe the data that has been generated, validated and submitted to the designated modENCODE database(s). Additional reporting on cost will also be required.

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

Sharing Research Data:Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Access to Research Data through the Freedom of Information Act:The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Sharing of Model Organisms:NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

NIH Public Access Policy:NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

URLs in NIH Grant Applications or Appendices:All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.